If factors related to access to care are not considered, the increased mortality from cardiovascular disease in African-Americans relative to other groups is due to the increased frequency of some diseases, a qualitatively different cardiac response to disorders affecting all ethnic groups and a relatively poor response to treatment of congestive heart failure. An undiagnosed, coexistent, relatively prevalent, treatment-resistant cardiomyopathy is a possible partial explanation. During the last four years we have shown that a genetically determined form of late-onset amyloidosis due to a substitution of ILE for VAL at position 122 in the serum protein transthyretin (TTR) contributes to this racial disparity. We have shown that the allele is extremely rare in individuals without documented African heritage. Its prevalence among African-Americans (3-4%) has been independently determined in the Northeast, Southeast, Midwest and Southwestern U.S. (as well in many regions of Africa). We have also obtained data indicating the allele frequency decreases in the community with increasing age, suggesting that it has an independent effect on mortality. The allele is present in 10% of African-Americans over 65 with New York Heart Association grade III and IV congestive heart failure, and is frequently unrecognized even by skilled cardiologists. In a current case control study the gene carriers show many of the characteristic clinical features of cardiac amyloidosis with a statistically significant greater frequency than the age, gender and ethnically matched controls. Our current proposal is designed to independently validate some of these findings as well as defining the rate of appearance of clinical features of the disease in an allele bearing cohort followed from an age prior to the appearance of disease to a time when they become clinically at risk. In conjunction with our colleagues in chemistry we have developed small molecules that can inhibit transthyretin amyloidogenesis in the test tube and in tissue culture. The currently proposed studies will characterize the natural history and clinical penetrance of the disease and will set the stage for clinical trials of compounds found to be effective in pre-clinical studies in both therapy and prophylaxis of this hereditary disorder encoded by a gene carried by 1-1.5 million African- Americans.African-Americans are at greater risk for cardiovascular disease than Caucasian- Americans. We have identified a gene that is present in 3-4% of African-Americans that is associated with a heart disease called cardiac amyloidosis appearing after age 60. We have shown that all the carriers of the gene have physical changes in the heart related to the disease but we have not yet determined if the changes are always associated with abnormal function. The present proposal will establish whether gene carriers have evidence for compromised cardiac function and which markers of abnormality can be used to measure progression or responsiveness to new therapeutics designed to prevent or reverse the process. [unreadable] [unreadable] [unreadable]